It is known that mammalian cells develop resistance to drugs, such as discovered in the field of cancer research where cancerous cells develop resistance to drugs used in chemotherapy. This resistance halts the effectiveness of the drugs used in chemotherapy for slowing down or ceasing the multiplication of the cancerous cells. Recently reported in Science, Vol. 221, pp 1285-1288, Sept. 1983, reference is made to hamster, mouse and human tumerous cell lines displaying multiple drug resistance. It was discovered that there is an increased expression of a 170,000-dalton surface antigen correlated with multidrug resistance as found in the cell membrane. The antigen has been isolated and is understood to be a P-glycoprotein.
Multidrug resistance (MDR) is the phenotype exhibited by mammalian cell mutants particularly selected for resistance to a certain anti-cancer drug, but also exhibiting resistance to a broad spectrum of other cancer drugs having different chemical structures and targets of action. Cells with this phenotype maintain reduced intracellular levels of drugs as the apparent mechanism of resistance. Related to this altered drug transport function, the plasma membranes of these cells contain elevated amounts of the polypeptide specifically referred to as P-glycoprotein.
It has been possible to select a variety of mutant cell lines with different degrees of drug resistance. The amount of P-glycoprotein in the plasma membranes of these different cell lines correlates quantitatively with the degree of drug resistance.
Over-expression of P-glycoprotein appears to be a consistent and characteristic feature of the multidrug resistance phenotype.
Extensive work has been conducted to demonstrate this P-glycoprotein directly or indirectly mediates the multidrug resistance phenotype. Extensive genetic studies have been carried out on Chinese hamster ovary cell systems as disclosed in Ling V., Kartner, N., Sudo, T., Siminovitch, L. and Riordan, J. R. Cancer Treat. Rep. 67, 869-874 (1983). In these studies, it is established that:
(a) independent drug resistant clones isolated in the single step without mutagenesis display the multidrug resistance phenotype and P-glycoprotein over-expression;
(b) selection for increased drug resistance, i.e., colchicine resulted in increased cross-resistance to other drugs and increased P-glycoprotein expression;
(c) revertants isolated in a single step for drug sensitivity to one compound involved in the multidrug resistance phenotype, displays reversion of the other aspects of the phenotype including reduced P-glycoprotein expression;
(d) cross-resistance, collateral sensitivity, and P-glycoprotein over-expression are concordantly expressed in cell:cell hybrids.
The unknown aspect with respect to the isolation of the P-glycoprotein and its determinant in causing multidrug resistance is whether or not a protein of this size is coded by a single gene or family of genes or the result of independent events in the selective expression of a gene or gene family.